Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

Background: It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods: We examined young, middle-aged, and older individuals with and without hearing threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), auditory steady-state responses (ASSRs), speech comprehension (OLSA), and syllable discrimination in quiet and noise. Results: A noticeable decline of hearing sensitivity in extended high-frequency regions and its influence on low-frequency-induced ABRs was striking. When testing for differences in OLSA thresholds normalized for PT thresholds (PTTs), marked differences in speech comprehension ability exist not only in noise, but also in quiet, and they exist throughout the whole age range investigated. Listeners with poor speech comprehension in quiet exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent of PTT, smaller and delayed ABRs, and lower performance in vowel-phoneme discrimination below phase-locking limits (/o/-/u/). When OLSA was tested in noise, listeners with poor speech comprehension independent of PTT had larger pDPOAEs and, thus, cochlear amplifier performance, larger ASSR amplitudes, and higher uncomfortable loudness levels, all linked with lower performance of vowel-phoneme discrimination above the phase-locking limit (/i/-/y/). Conslusions: This study indicates that listening in noise in humans has a sizable disadvantage in envelope coding when basilar-membrane compression is compromised. Clearly, and in contrast to previous assumptions, both good and poor speech comprehension can exist independently of differences in PTTs and age, a phenomenon that urgently requires improved techniques to diagnose sound processing at stimulus onset in the clinical routine.

Before hearing onset, inner hair cell (IHC) maturation proceeds under the influence of spontaneous Ca²⁺ action potentials (APs). The temporal signature of the IHC Ca²⁺ AP is modified through an efferent cholinergic feedback from the medial olivocochlear bundle (MOC) and drives the IHC pre- and post-synapse phenotype towards low spontaneous (spike) rate (SR), high-threshold characteristics. With sensory experience, the IHC pre- and post-synapse phenotype matures towards the instruction of low-SR, high-threshold and of high-SR, low-threshold auditory fiber characteristics. Corticosteroid feedback together with local brain-derived nerve growth factor (BDNF) and catecholaminergic neurotransmitters (dopamine) might be essential for this developmental step. In this review, we address the question of whether the control of low-SR and high-SR fiber characteristics is linked to various degrees of vulnerability of auditory fibers in the mature system. In particular, we examine several IHC synaptopathies in the context of various hearing disorders and exemplified shortfalls before and after hearing onset.

Voltage-gated L-type Ca²⁺ channels (L-VGCCs) like Ca_V1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC Ca_V1.3, Ca_V1.2 is also expressed. Due to lethality of constitutive Ca_V1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of Ca_V1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of Ca_V1.2 on the cochlea from that on feedback loops from higher auditory centers Ca_V1.2 was deleted, in one mouse line, under the Pax2 promoter (Ca_V1.2^Pax2) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting Ca_V1.2 (Ca_V1.2^Egr2) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the Ca_V1.2^Pax2 mice, but not in the Ca_V1.2^Egr2 mice. After noise exposure, Ca_V1.2^Pax2 mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in Ca_V1.2^Pax2 mice, we suggest that a Ca_V1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of Ca_V1.2 function in efferent circuits.

The unconventional myosin VI, a member of the actin-based motor protein family of myosins, is expressed in the retina. Its deletion was previously shown to reduce amplitudes of the a- and b-waves of the electroretinogram. Analyzing wild-type and myosin VI-deficient Snell’s Waltzer mice in more detail, the expression pattern of myosin VI in retinal pigment epithelium, outer limiting membrane, and outer plexiform layer could be linked with differential progressing ocular deficits. These encompassed reduced a-waves and b-waves and disturbed oscillatory potentials in the electroretinogram, photoreceptor cell death, retinal microglia infiltration, and formation of basal laminar deposits. A phenotype comprising features of glaucoma (neurodegeneration) and age-related macular degeneration could thus be uncovered that suggests dysfunction of myosin VI and its variable cargo adaptor proteins for membrane sorting and autophagy, as possible candidate mediators for both disease forms.

Age-related decoupling of auditory nerve fibers from hair cells (cochlear synaptopathy) has been linked to temporal processing deficits and impaired speech recognition performance. The link between both is elusive. We have previously demonstrated that cochlear synaptopathy, if centrally compensated through enhanced input/output function (neural gain), can prevent age-dependent temporal discrimination loss. It was also found that central neural gain after acoustic trauma was linked to hippocampal long-term potentiation (LTP) and upregulation of brain-derived neurotrophic factor (BDNF). Using middle-aged and old BDNF-live-exon-visualization (BLEV) reporter mice we analyzed the specific recruitment of LTP and the activity-dependent usage of Bdnf exon-IV and -VI promoters relative to cochlear synaptopathy and central (temporal) processing. For both groups, specimens with higher or lower ability to centrally compensate diminished auditory nerve activity were found. Strikingly, low compensating mouse groups differed from high compensators by prolonged auditory nerve latency. Moreover, low compensators exhibited attenuated responses to amplitude-modulated tones, and a reduction of hippocampal LTP and Bdnf transcript levels in comparison to high compensators. These results suggest that latency of auditory nerve processing, recruitment of hippocampal LTP, and Bdnf transcription, are key factors for age-dependent auditory processing deficits, rather than cochlear synaptopathy or aging per se.